Insights into the interaction dynamics between volatile anesthetics and tubulin through computational molecular modelling

Abstract

General anesthetics, able to reversibly suppress all conscious brain activity, have baffled medical science for decades, and little is known about their exact molecular mechanism of action. Given the recent scientific interest in the exploration of microtubules as putative functional targets of anesthetics, and the involvement thereof in neurodegenerative disorders, the present work focuses on the investigation of the interaction between human tubulin and four volatile anesthetics: ethylene, desflurane, halothane and methoxyflurane. Interaction sites on different tubulin isotypes are predicted through docking, along with an estimate of the binding affinity ranking. The analysis is expanded by Molecular Dynamics simulations, where the dimers are allowed to freely interact with anesthetics in the surrounding medium. This allowed for the determination of interaction hotspots on tubulin dimers, which could be linked to different functional consequences on the microtubule architecture, and confirmed the weak, Van der Waals-type interaction, occurring within hydrophobic pockets on the dimer. Both docking and MD simulations highlighted significantly weaker interactions of ethylene, consistent with its far lower potency as a general anesthetic. Overall, simulations suggest a transient interaction between anesthetics and microtubules in general anesthesia, and contact probability analysis shows interaction strengths consistent with the potencies of the four compounds.

Communicated by Ramaswamy H. Sarma

Keywords:

• Volatile anesthetics
• molecular dynamics
• molecular docking
• tubulin
• microtubules
• cytoskeleton

Acknowledgements

We acknowledge the CINECA award under the ISCRA initiative, for the availability of high-performance computing resources and support.

Conflicts of interest

The authors declare no conflict of interest.

Funding

This research received no external funding.

Author contributions

EAZ carried out the docking and molecular dynamics simulations and the subsequent analyses, interpreted and rationalized the results and wrote the paper. MD and JAT designed the study, interpreted the results and proof-read the paper. MC provided supervision about general anesthetics and their properties and clinical caveats, and interpreted the results.

Data availability

All data supporting the findings of the study are available from the corresponding author, JAT, upon reasonable request.